The Toll-like receptor 4 (TLR4) antagonists, (+)-naloxone and (+)-naltrexone, have been reported to decrease self-administration of opioids in rats and to reduce other preclinical indicators of abuse potential. However, under the self-administration conditions studied, the effects of TLR4 antagonists were not reinforcer selective, questioning the involvement of those receptors and their mediated inflammatory response specifically in opioid abuse. The objectives of the current study were to further characterize the reinforcer specificity of TLR4 antagonism in opioid self-administration and to explore its effects in a preclinical model of craving/relapse...

Understanding the neurobiological basis of post-traumatic stress disorder (PTSD) is fundamental to accurately diagnose this neuropathology and offer appropriate treatment options to patients. The lack of pharmacological effects, too often observed with the most currently used drugs, the selective serotonin reuptake inhibitors (SSRIs), makes even more urgent the discovery of new pharmacological approaches. Reliable animal models of PTSD are difficult to establish because of the present limited understanding of the PTSD heterogeneity and of the influence of various environmental factors that trigger the disorder in humans...

In this review, we advocate a dimensional approach on the basis of candidate endophenotypes to the development of animal models of post-traumatic stress disorder (PTSD) capable of including genetic liability factors, variations in symptoms profile and underlying neurobiological mechanisms, and specific comorbidities. Results from the clinical literature pointed to two candidate endophenotypes of PTSD: low sensory gating and high waiting impulsivity. Findings of comparative studies in mice of two inbred strains characterized by different expressions of the two candidate endophenotypes showed different strain-specific neural and behavioral effects of stress experiences...

Ketamine has been shown to induce a rapid antidepressant effect on patients with depression. In many animal models, both rapid and sustained antidepressant activities were also found in response to an antagonist of group II metabotropic glutamate receptors, LY341495, and its mechanism of action seemed to be similar in many ways to the action of ketamine. It has also been found that LY341495 enhanced the antidepressant-like activity of sub-effective doses of ketamine in rats without inducing adverse effects...

Activation of muscarinic receptors in the brain antagonizes the actions of cocaine, blocking both its discriminative stimulus and reinforcing properties. Pilocarpine is a nonselective muscarinic agonist that is used clinically, but has not been well characterized for its actions during cocaine-reinforced behavior. This study evaluated its effects on cocaine-reinforced and food-reinforced behaviors in rats, using the cholinesterase inhibitor tacrine as a comparator. Intraperitoneal pilocarpine or tacrine at doses of 1...

Pain is a significant public health problem, and assessment of pain-related impairment of behavior is a key clinical indicator and treatment target. Similar to opioids and NSAIDs, dopamine (DA) transporter inhibitors block pain-related depression of intracranial self-stimulation (ICSS) in rats. The primary goal of the present study was to determine if the effects of monoamine uptake inhibitors on pain-related depression of ICSS in rats extend to an assay of pain-related depression of nesting in mice. We hypothesized that the DA transporter-selective uptake inhibitor bupropion would block depression of nesting behavior produced by intraperitoneal injection of lactic acid, whereas selective serotonin transporter-selective citalopram, norepinephrine transporter-selective nisoxetine, and the mixed action selective serotonin transporter/norepinephrine transporter inhibitor milnacipran would be ineffective...

Early-life stress (ELS) is known to exert long-term effects on brain function, with resulting deleterious consequences for several aspects of mental health, including the development of addiction to drugs of abuse. One potential mechanism in humans is suggested by findings that ELS interacts with polymorphisms of the GABRA2 gene, encoding α2 subunits of GABAA receptors, to increase the risk for both post-traumatic stress disorder and vulnerability to cocaine addiction. We used a mouse model, in which the amount of material for nest building was reduced during early postnatal life, to study interactions between ELS and expression of α2-containing GABAA receptors in influencing cocaine-related behaviour...

Obsessive-compulsive disorder (OCD) is considered a heterogeneous anxiety disorder that includes compulsions. Celecoxib is considered an adjuvant to fluoxetine in the management of OCD in a clinical study. However, the experimental evidence is yet to be established. Therefore, the antianxiety and anticompulsive-like activity of celecoxib (20 mg/kg, orally) was evaluated in the presence or absence of fluoxetine (20 mg/kg, orally) in mice who were exposed to chronic unpredictable mild stress (CUMS) for 14 consecutive days...

Maternal stress and early life stress affect development. Zebrafish (Danio rerio) are ideally suited to study this, as embryos develop externally into free-feeding larvae. The objective of this study was therefore to assess the effects of increased levels of cortisol, mimicking thereby maternal stress, on larval physiology and behaviour. We studied the effects in two common zebrafish strains, that is, AB and Tupfel long-fin (TL), to assess strain dependency of effects. Fertilized eggs were exposed to a cortisol-containing medium (1...

Few studies have explored the effects of the combined use of alcohol and cigarette in humans, despite its prevalence. Here we evaluated the effect of isolated and combined use on behaviors and neuronal parameters in rats. Male adult rats were divided into alcohol (AL, 2 g/kg, by oral gavage), cigarette smoke (TB, six cigarettes, by inhalation), combined use (ALTB), or control (CT, water by oral gavage and environmental air) groups, treated twice a day (09.00 and 14.00 h). After 4 weeks, the rats were tested in the open field for behavioral analysis and euthanized for brain volume estimation and counting of neurons in the hippocampus...

Opioid addiction is one of the most crucial issues in the world. Opioid abuse by parents makes children more prone to many psychological disorders such as drug addiction. Therefore, this study was carried out to examine the effect of morphine exposure 10 days before gestation on morphine and methamphetamine preference in male offspring. Adult Wistar rats (male and female) received morphine orally for 21 days and were drug free for 10 days. Thereafter, they were allowed to mate with either a morphine-abstinent or drug-naive rat...

Most people have or will experience traumatic stress at some time over the lifespan, but only a subset of traumatized individuals develop post-traumatic stress disorder (PTSD). Clinical research supports high rates of traumatic brain injury (TBI)-PTSD comorbidity and demonstrates TBI as a significant predictor of the development of PTSD. Biological factors impacted following brain injury that may contribute to increased PTSD risk are unknown. Heightened stress reactivity and dysregulated hypothalamic-pituitary-adrenal (HPA) axis function are common to both TBI and PTSD, and affect amygdalar structure and function, which is implicated in PTSD...

This study examined effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 in an assay of pain-related behavioral depression. Adult, male Sprague-Dawley rats responded for electrical brain stimulation in a frequency-rate intracranial self-stimulation (ICSS) procedure. Intraperitoneal injection of 1.8% lactic acid served as an acute noxious stimulus to depress ICSS. Effects of KRM-II-81 were evaluated in the absence and presence of the acid noxious stimulus. The NSAID ketorolac and the benzodiazepine diazepam were tested as comparators...

Serotonin, one of the first neurotransmitters to be identified, is an evolutionarily old molecule that is highly conserved across the animal kingdom, and widely used throughout the brain. Despite this, ascribing a specific set of functions to brain serotonin and its receptors has been difficult and controversial. The 2A subtype of serotonin receptors (5-HT2A receptor) is the major excitatory serotonin receptor in the brain and has been linked to the effects of drugs that produce profound sensory and cognitive changes...

Catalepsy - an immobile state in which individuals fail to change imposed postures - can be induced by haloperidol. In rats, the pattern of haloperidol-induced catalepsy is very similar to that observed in Parkinson's disease (PD). As some PD symptoms seem to depend on the patient's emotional state, and as anxiety disorders are common in PD, it is possible that the central mechanisms regulating emotional and cataleptic states interplay. Previously, we showed that haloperidol impaired contextual-induced alarm calls in rats, without affecting footshock-evoked calls...

This study evaluated the procognitive effects of S 38093 (a new inverse agonist of the histaminergic H3 receptor) and S 47445 (a new α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) in 2-3-month-old Swiss mice as compared with donepezil and memantine, two main reference compounds in the treatment of Alzheimer's disease. The object recognition task allows the study of natural forgetting and is classically used in assessing drug effects on memory. Here, we show that mice exhibit significant object recognition at short (15 min) but not long (24 h) retention intervals separating the familiarization and recognition phases...

Neuropathic pain is driven by abnormal peripheral and central processing, and treatments are insufficiently effective. Antibodies against nerve growth factor (anti-NGF) have been investigated as a potent analgesic treatment for numerous conditions. However, the peripheral and brain effects of anti-NGF in neuropathic pain remain unknown. We examined the effectiveness of anti-NGF in reducing chronic pain by local administration in a rat model of sciatic constriction injury (CCI). NGF and substance P in the dorsal root ganglion (DRG) and spinal cord were evaluated...

The Tinkertoy test (TTT) has often been used to assess executive function. Despite its clinical importance, there are few published normative data for it. Thus, the primary aim of this study was to fill this gap. Moreover, as there exists a sex difference in many cognitive abilities and neuropsychological tests, a secondary aim was to examine whether sex influences TTT performance. We administered the TTT to 25 healthy men and 25 healthy women whose average age was 28 years. Performances were scored based upon Lezak's (1982) original TTT criteria...

Stimulant drugs used for treating attention-deficit hyperactivity disorder (ADHD) increase signal-detection accuracy in five-choice serial reaction-time procedures. These increases may result from drug-induced increases in control exerted by the stimuli that prompt responses, which was assessed in the present study. Mice were trained with food reinforcement to nose poke into one of five holes after its illumination (signal), and effects of methylphenidate, d-amphetamine, and pentobarbital were assessed. Subsequently, the time from trial onset to signal was changed from fixed to variable for one group of subjects...